This application lists 5 specific aims intended to further define the anatomy, biochemistry, pharmacology, physiology and function of the sensory innervation of cephalic blood vessels. We have previously postulated that such a system is importantly involved in the pathophysiology of vascular headaches and have recent data to suggest that this system becomes modified by the presence of blood in the subarachnoid space. A multidisciplinary approach will explore the aims using a) axonal transport studies, immunohistochemistry and in situ hybridization studies to further determine the neural connectivity between perivascular sensory fibers surrounding dural and pial arteries, cell bodies in dorsal root and trigeminal ganglia, and central endings in brain stem; b) vascular permeability studies in dura will use iodinated albumin or horseradish peroxidase to define the relationship between perivascular afferents and the observed enhanced permeability in dura following chemical injections, electrical trigeminal stimulation or sensitization responses. The already-noted potent inhibitory effects of ergot alkaloids and neurotransmitter agonists and receptor blockers on the natural history of this leakage will be further defined mechanistically, c) the effects of adding blood into the subarachnoid space on sensory transmitter levels and peptide synthesis within blood vessels and sensory ganglia will be characterized by RIA and the mechanisms clarified (insitu and Northern blot analysis) to extend our preliminary data showing significant disruption in neurotransmitter turnover shortly after the induction of hemorrhage. By taking such an approach, we hope to explore the possible roles for the trigeminovascular system in cerebrovascular regulation during health and disease.